Increased osteoclast differentiation is the primary mechanism responsible for most conditions that cause chronic bone loss. Thus, improved understanding of the pathogenesis responsible for these conditions requires detailed knowledge of osteoclast differentiation. Osteoclast differentiation is stimulated by contact with a layer of mesenchymal support cells, which are relatively immature members of the osteoblast lineage. We have recently shown that the effect of contact with the mesenchymal cell layer reflects production by the mesenchymal cells of both extracellular matrix and cell surface molecules. Although one of these molecules, RANKL, has recently been identified, the nature of other extracellular matrix/cell surface molecules that are involved in this process is incompletely understood. This project will test the hypothesis that specific cell surface and/or extracellular matrix molecules in addition to RANKL are produced by mesenchymal cells to support osteoclast differentiation. For this purpose, we will utilize phage display libraries to select peptides that specifically bind to the mesenchymal cells that support osteoclast differentiation, determine which of the peptides regulate osteoclast differentiation, and identify the extracellular matrix/cell surface molecules that bind to these peptides. This project will provide significant new information on the extracellular matrix/cell surface molecules produced by mesenchymal cells in order to support osteoclast differentiation. This project will also identify novel peptides that specifically inhibit osteoclast differentiation and that,therefore, may be useful starting points for a peptidomimetic drug discovery program aimed at conditions of chronic bone loss.